Levofloxacin, a synthetic broad-spectrum antibacterial agent for oral and intravenous administration, chemically is a chiral fluorinated carboxyquinolone. The chemical name of the hemihydrate form is (−)-(S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2, 3-dihydro-7H-pyrido-[1,2,3-de] [1,4] benzoxazine-6-carboxylic acid hemihydrate (CAS Registry No. 138199-71-0).

Levofloxacin is 8-128 times more potent in inhibiting the multiplication of gram-positive and gram-negative bacteria than its (+)-enatiomer, and approximately 2 times more active than its racemate, ofloxacine.
Three polymorphic forms (anhydrous α, β and γ) and two pseudopolymorphic forms (hemihydrate and monohydrate) of levofloxacin are reported by Kitaoka, H. et al in Chem. Pharm. Bull. 43 (4): 649 (1995). Levofloxacin hemihydrate is superior to the monohydrate as a drug substance in term of phase stability, one of the most important physical properties for pharmaceuticals.
The disclosed methods in JP-A-62-252790 or EP-0206283B for producing levofloxacin by means of crystallization of crude product from a solvent mixture of ethyl alcohol and ethyl ether or ammonia aqueous/ethanol solution may result in a mixture of levofloxacin hemihydrate and levofloxacin monohydrate.
To convert the formed monohydrate to hemihydrate is not practical. Although the contained water in the monohydrate can be vaporized via heating the crystals to result in the anhydrous form, which will absorb moisture, the anhydrous form only returns back to the original monohydrate, not the hemihydrate.
JP 2006111561 discloses a method of directly converting levofloxacin monohydrate to hemihydrate in tetrahydrofuran containing only 0.005% water. However, the yield is only 61%. The disadvantages are clear, an extra-manipulation step and loss of nearly 40% of the product.
To remove the monohydrate from contaminated levofloxacin hemihydrate via multiple recrystalizations is very labor and time intensive since both have very close solubility in solvents. Therefore, the recrystallization approach is impractical for manufacturing purposes.
The third solid state, the anhydrous crystal, is obtained by completely driving off crystal water from either the mono- or hemi-hydrate under elevated temperature. The anhydrate exhibits the problems of blockage and stickiness during industrial formulation processing. Thus, the dehydration of the hemi- and monohydrates is typically avoided by manufacturers.
U.S. Pat. No. 5,545,737 reports a method for selectively producing levofloxacin hemihydrate or monohydrate by controlling the water content of an aqueous solvent in which levofloxacin is dissolved during crystal formation. A single solvent such as ethanol, methanol, 1-propanol, 2-propanol or acetone is selected for the purpose.
WO 03/028664 discloses methods to produce crystal forms A, B, C, F, G, H as well as levofloxacin hemihydrate.
WO 03/045329 discloses slightly modified methods to purify levofloxacin hemihydrate via raising the dissolving temperature and adding an antioxidant such as metabisulfite or ascorbic acid into the crystallization solvent.
The methods given in WO 03/028664 and WO 03/045329 for preparing levofloxacin hemihydrate have disadvantages. The crude product is dissolved and heated in a solvent such as dimethylsulfoxide (DMSO, boiling point (bp) 189° C.), dimethyl acetamide (DMA, bp 164-166° C.), propylene-glycol-monomethyl ether (bp 118-119° C.), or n-BuOH (bp 117-118° C.) with/without water. Three potential risks may accompany these methods. The undesired monohydrate form may form during crystallization at high reflux temperatures.
The hemihydrate may also be converted to the undesired anhydrous form during the course of removing the high boiling point solvents attached on the wet product under high temperatures and extended drying times. It is noted that U.S. Pat. No. 5,545,737 discloses the result of differential thermal analysis indicates that crystal water is liberated from the hemi- or mono-levofloxacin at about 70° C. under atmospheric pressure or at 60° C. under reduced pressure.
The possibility of contamination caused by residual antioxidant in the final product may occur and may interfere with the purity of the product.
Furthermore, acetonitrile used in the process of WO 03/028664 and WO 03/045329 belongs to Class II category listed in the Guidance for Industry, Q3C Impurities: Residual Solvents, U.S. Food and Drug Administration. As a Class II solvent, it is less desirable for use in the preparation of pharmaceutical products because of its inherent toxicity.
The yields of WO 03/028664 and WO 03/045329 for the crystallization are only in the range of 31-84%.
WO 2006/009374 A1 discloses a process for preparing levofloxacin hemihydrate or monohydrate of high purity. The purification experiments are operated in a mixed solvent system consisting of two organic solvents selected from ethyl acetate, methyl acetate, isobutyl methyl ketone, t-butyl alcohol and water. To overcome the difficulty of low solubility of the crude product in the solvent mixture, large volumes of organic solvents are needed, which greatly reduces the unit manufacturing capacity of reactors and increases the solvent consumption and labor costs.
WO 2006/048889 describes a process to prepare the hemihydrate in high purity. The complicated process includes pH-adjustments (4 times), de-colorizations (2 times), extraction with chlorinated solvent, such as dichloromethane (a Class II solvent), and crystallization in tetrahydrofuran (also a Class II solvent).
Of the described documents, the reported yields of crystal formation of levofloxacin hemihydrate are only around 70% to 85%. Low yield may partially be due to the loss of the product dissolved in large volumes of mother liquid.
Accordingly, there remains a need for a better process for manufacturing levofloxacin hemihydrate and related pyridobenzoxazine carboxylic acid hemihydrates.